Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoEnull Mice

Abstract

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Plasmatic NT-proBNP concentrations in patients with coexistent periodontal disease and congestive heart failure: pilot studies

“…Previous studies, by increasing the effectiveness of treatment and ensuring the comfort of the patient [6,37,38]. The results of this pilot study require confirmation based on trials in larger groups of patients.…”

Apolipoprotein E Related Co-Morbidities and Alzheimer’s Disease

“…This primary environmental risk factor (infection) has the potential for pathogenic interplay in the hetero/homozygous apoε4 genotype via initiation of an intrinsic cascade of risk factors (infection>inflammation) for dyslipidaemia. Another common feature of all the mono and polyinfected experiments in ApoE −/− mice [71,75] was the abundant expression of NPY gene in vascular tissues [75]. This suggests an intricate relationship of NPY gene and chronic infections with possible manifestation for the development of insulin resistance as discussed below.…”

“…Nevertheless, there is a suggestion of an emerging role of NPY gene that may be of relevance to this metabolic syndrome via its effect on the HPA activity as demonstrated by ApoE −/− mice following an oral infection [75].…”

Invasions of Host-Associated Microbiome Networks

“…These invaders are often ineffective WH colonisers (or less virulent) unless they are together with other specific taxa. For instance, to test the hypothesis that periodontitis (gum disease) is caused by a disbiotic microbial community, mice were infected with four different bacteria species simultaneously and compared them to mono-infections (Chukkapalli et al 2015). They found that polymicrobial infections were more virulent, formed plaques more readily and altered immunity functioning.…”